miR-182-5p and miR-378a-3p regulate ferroptosis in I/R-induced renal injury

Abstract

Renal tubular cell death is the key factor of the pathogenesis of ischemia/reperfusion (I/R) kidney injury. Ferroptosis is a type of regulated cell death (RCD) found in various diseases. However, the underlying molecular mechanisms related to ferroptosis in renal I/R injury remain unclear. In the present study, we investigated the regulatory role of microRNAs on ferroptosis in I/R-induced renal injury. We established the I/R-induced renal injury model in rats, and H/R induced HK-2 cells injury in vitro. CCK-8 was used to measure cell viability. Fe2+ and ROS levels were assayed to evaluate the activation of ferroptosis. We performed RNA sequencing to profile the miRNAs expression in H/R-induced injury and ferroptosis. Western blot analysis was used to detect the protein expression. qRT-PCR was used to detect the mRNA and miRNA levels in cells and tissues. We further used luciferase reporter assay to verify the direct targeting effect of miRNA. We found that ischemia/reperfusion-induced ferroptosis in rat’s kidney. We identified that miR-182-5p and miR-378a-3p were upregulated in the ferroptosis and H/R-induced injury, and correlates reversely with glutathione peroxidases 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11) expression in renal I/R injury tissues, respectively. In vitro studies showed that miR-182-5p and miR-378a-3p induced ferroptosis in cells. We further found that miR-182-5p and miR-378a-3p regulated the expression of GPX4 and SLC7A11 negatively by directly binding to the 3′UTR of GPX4 and SLC7A11 mRNA. In vivo study showed that silencing miR-182-5p and miR-378a-3p alleviated the I/R-induced renal injury in rats. In conclusion, we demonstrated that I/R induced upregulation of miR-182-5p and miR-378a-3p, leading to activation of ferroptosis in renal injury through downregulation of GPX4 and SLC7A11.

miR-3587 Targets HMOX1 to Attenuate Ferroptotic Renal Injury Following Ischemia-Reperfusion

“…Ding et al further con rmed that hypoxia-reoxygenation was able to promote the upregulation of miR-182-5p and miR-378a-3p in renal tubular epithelial cells in vitro, resulting in glutathione peroxidase 4 (GPX4) and SLC7A11 downregulation and consequent ferroptotic injury. Consistently, silencing these two miRNAs in an in vivo rat renal IR model system was su cient to suppress ferroptotic renal injury [10]. However, further work is required to fully elucidate the regulatory roles of individual miRNAs in the context of ferroptosis-induced renal IR injury.…”

“…miRNAs can serve as key regulators of gene expression [7], and both miRNA mimics and inhibitors have been highlighted as promising therapeutic tools in preclinical contexts [27]. Studies have shown that ischemia-reperfusion conditions result in the upregulation of miR-182-5p and miR-378a-3p, activating ferroptotic renal injury by downregulating GPX4 and SLC7A11 [10]. However, there have been relatively few prior analyses of how miRNAs modulate ferroptotic injury in the context of renal IR, and there have been no reports regarding miRNA-mediated HMOX1 regulation.…”

Increased hypospadias risk by GREM1 rs3743104[G] in the southern Han Chinese population

“…we identified that miR-182 could target the seeding region spanning rs3743104 at the 3′-UTR of GREM1 , which suppresses the transcription of GREM1 . miR-182 has been reported as a biomarker for kidney injury and bladder cancer, and a regulatory miRNA binding to 3′-UTR of gene targets to the progression of diseases [ 32 , 33 ]. It's worthy of further work that how miR-182 is regulated.…”

Ferroptosis: A Novel Therapeutic Target for Ischemia-Reperfusion Injury

“…Ferrostatin-1 Inhibit lipid peroxidation myocardial, cerebral, and liver I/R injury Tuo et al, 2017;Fang et al, 2019;Yamada et al, 2020 Dexrazoxane Chelation of iron myocardial I/R injury Fang et al, 2019 Deferoxamine Reduce intracellular iron myocardial, cerebral, liver, and testicular I/R injury Hanson et al, 2009;Li et al, 2018;Yamada et al, 2020;Tu et al, 2021 Liproxstatin-1 Inhibit lipid peroxidation myocardial, cerebral, liver, intestinal, pulmonary, and testicular I/R injury Friedmann Angeli et al, 2014;Tuo et al, 2017;Li et al, 2018;Feng et al, 2019;Li Y. et al, 2019;Xu et al, 2020 MicroRNAs (miRNAs) are a class of small non-coding RNAs that function in various biological processes involving cell death. In I/R-induced renal injury, miR-182-5p and miR-378-3p are upregulated, which promotes the activation of ferroptosis through the downregulation of GPX4 and SLC7A11 (Ding et al, 2020), indicating that ferroptosis may be regulated by multiple I/R-related miRNAs and targeting these miRNAs could provide novel therapeutic methods to suppress ferroptosis and I/R injury.…”

“…MicroRNAs (miRNAs) are a class of small non-coding RNAs that function in various biological processes involving cell death. In I/R-induced renal injury, miR-182-5p and miR-378-3p are upregulated, which promotes the activation of ferroptosis through the downregulation of GPX4 and SLC7A11 ( Ding et al, 2020 ), indicating that ferroptosis may be regulated by multiple I/R-related miRNAs and targeting these miRNAs could provide novel therapeutic methods to suppress ferroptosis and I/R injury.…”